Pharmacogenetics Research Network and Knowledge Base Third Scientific Meeting Alison F
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Meeting Report 437 Pharmacogenetics Research Network and Knowledge Base Third Scientific Meeting Alison F. Davisa and Rochelle M. Longb Pharmacogenetics 2003, 13:437–440 Keywords: PharmGKB, pharmacogenetics, pharmacogenomics, National Institutes of Health, population genetics aOffice of Communications and Public Liaison and bDivision of Pharmacology, Physiology and Biological Chemistry, National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Maryland, USA. Correspondence and requests for reprints to Rochelle M. Long, Division of Pharmacology, Physiology and Biological Chemistry, 45 Center Dr., Rm. 2AS-49G, National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD 20892-6200, USA. Tel: +301 594 1826; fax: +301 480 2802; e-mail: [email protected] Received 2 April 2003 Accepted 10 May 2003 Introduction Quantitative and analytical challenges in The Pharmacogenetics Research Network and Know- genetics research ledge Base (PGRN) held its third annual open scientific While the history of pharmacogenetics research dates meeting on 3 March 2003 in Memphis, Tennessee. back nearly 50 years, changes in the scientific landscape The PGRN effort is a nationwide pharmacogenetics have refocused attention on current challenges facing research initiative sponsored by the National Institutes this field. Investigating multigenic human variation, of Health. Network members submit data to a compre especially as it relates to the molecular basis of complex hensive knowledge base, PharmGKB (http://www. diseases, is a critical element of modern genetics pharmGKB.org/). The meeting focused on the analyti research. While Mendelian disease genes are typically cal and quantitative issues confronting modern genetics of recent origin and alleles have large phenotypic research. Morning sessions addressed population genet effects, complex disease traits are often characterized ics, analytical challenges in molecular epidemiology by alleles exerting small phenotypic effects. In studying and comparative genomics. Afternoon sessions featured complex diseases, Aravinda Chakravarti of The Johns selected research updates from PGRN investigators. Hopkins University School of Medicine noted that functional tests of alleles and gene interactions must The PGRN was conceived as a network of multidisci complement gene mapping efforts, and that an essen plinary, collaborative research groups of investigators tial component of these studies is recapitulation of the examining how genetic variation contributes to inter- disease trait in an experimental system. Good study individual differences in drug responses. The groups design can tease apart the many factors that produce a are charged with collecting comprehensive, integrative complex disease, including episodic and age-dependent information about proteins and gene families known to traits; gender, environment and lifestyle; unknown be important in mediating the effects of therapeutics, gene actions; positive or negative regulatory alleles; and from variations in drug metabolizing enzymes to target epigenetic phenomena. receptors. Once comprehensive biological information for particular proteins and genes and their correspond Chakravarti described recent data from his group on ing variants is known, the network will catalogue this the complex genetics of Hirschsprung disease, in which information in a manner that is accessible and inter pedigree studies of Mennonite populations combined pretable to a wide range of scientists. PharmGKB has with a genome-wide association screen have recently the capacity to collect genetic sequence information, revealed two haplotypes in the receptor tyrosine kinase display polymorphic forms, identify functional conse (RET) gene [2]. Although variant alleles of several quences of genetic variation and rigorously correlate genes have been associated with this condition, none is this information with clinical drug responses [1]. necessary or sufficient to cause Hirschsprung disease. 0960-314X & 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.fpc.0000054101.48725.49 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 438 Pharmacogenetics 2003, Vol 13 No 7 Chakravarti reported that linkage disequilibrium stud about variation in drug metabolizing enzymes, as well ies have uncovered a genetic interaction between the as to impact the design and interpretation of preclinical endothelin receptor B (EDNRB) gene and multiple investigations. Anna Di Rienzo of the University of RET loci, and that preferential transmission of haplo Chicago discussed comparative genomics approaches to types may contribute to the phenotype of this disease. resequencing studies, in which the same sequence block is analysed in multiple individuals. Di Rienzo Michael Province of Washington University in St Louis described ongoing efforts of the Pharmacogenetics of discussed means to controlling type I error in statistical Anticancer Agents Research Group to clarify the genet data analysis. Province described the trade-offs inherent ic basis for toxicity in response to irinotecan and to selecting genotyping strategies, noting that research flavopiridol therapy. Comparative genomics analyses in ers pay a statistical penalty for excessive genotyping. the human, dog, rat, mouse and primate versions of the More data do not necessarily imply more information UGT1A gene cluster have begun to identify conserved and, for any complex trait, most genetic variation is regions, using the MultiPipMaker computational tool noise (including that present in candidate genes). To (http://bio.cse.psu.edu/pipmaker) [6]. This Web-based help explain the phenomenon, Province presented an tool draws percentage identity plots (pips) by compar analogy describing catching tuna with a fishing net, ing several genomic sequences, then creating align through which an occasional dolphin passes. In this ments and identifying nucleotide identities. One of the case, the tuna represent the test hypothesis, and the technique’s strengths is its unbiased analysis of any dolphins are the null hypothesis. In the example, larger DNA sequence, regardless of whether the sequence is and more prevalent passage of dolphins constitutes coding or non-coding. Di Rienzo predicted that future ‘noise’; however, increasing the fineness of the net (e.g. enhancements to comparative genomics strategies by applying a Bonferroni correction) severely restricts would include methods to assess statistical significance, data collection such that hardly any tuna can swim large-scale studies to measure functional significance through the net. This type of statistical correction can and new techniques to take into account phylogenetic produce a large power loss, restricting the utility of distances between compared species. such an approach. PGRN research update Province suggested that pharmacogenetics research Selected members of the PGRN groups presented demands a separation between gene discovery and recent research findings on adrenergic pharmacology, hypothesis testing. An approach pioneered in the 1940s membrane transporters and the pharmacogenomics of by Hungarian mathematician Abraham Wald led to the chemotherapy and asthma treatment. development of a current technique called sequential multiple decision procedures, which can help remedy Stephen Liggett of the University of Cincinnati pre the problem of balancing false positives (type I error) sented recent findings on a synergistic interaction be- and false negatives (type II error). Using this method tween â1 and Æ2C-adrenergic receptor polymorphisms lets the experimental data determine the point at which that may contribute to the pathology of congestive a hypothesis-generation phase should move to a true heart failure. G protein-coupled receptors constitute hypothesis-testing phase [3,4]. The approach helps to the largest family of signalling molecules, many of optimize sample size, while limiting both false positives which are involved in conveying drug action. Substan and false negatives. tial interindividual variation exists in agonist and antagonist response directed to these receptors; the Joseph Terwilliger of Columbia University contrasted known variable response to â-blocker therapy repre the goals and approaches of genetics and epidemiology. sents a particularly relevant topic for pharmacogenetics Whereas epidemiology is hypothesis-based and an investigation. Some of this variation may be attributed ascertainment bias is undesirable, genome-scanning to polymorphisms in coding regions, which may act experiments are hypothesis-free and an ascertainment together to provide persistent adrenergic stimulation bias is necessary to maximize the efficiency of mapping and promote heart failure and/or cardiac hypertrophy. studies. Genetic studies with small sample sizes tend to Liggett described a small clinical study in which control systematically overestimate linkage disequilibrium and or heart failure patients were genotyped at both the â1 underestimate variation [5]. Terwilliger expressed the and Æ2C-adrenergic receptor loci. Logistic regression view that genetic approaches need an ascertainment analysis was used to determine the potential effect of bias because penetrance is not equivalent to detection, each genotype and the interaction between them on and that genome-scanning methods should be limited the risk of heart failure. Data acquired from the African to generating hypotheses, not to testing